Alström Syndrome

What it is & clinical trials

What is Alström Syndrome?

Alström syndrome is a rare inherited autosomal recessive syndrome characterized by the onset of obesity in childhood or adolescence, Type 2 diabetes with severe insulin resistance, dyslipidemia, hypertension and severe multi-organ fibrosis, involving the liver, kidney and heart.

Alström syndrome is also characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs.Most patients with Alström Syndrome initially present with progressive visual impairment, hearing loss and obesity starting from birth, followed by type 2 diabetes mellitus and multiple other symptoms.

Patients with Alström syndrome develop fibrosis in multiple organs, including the heart, liver, kidneys and adipose tissue. The clinical manifestations of Alström syndrome vary in severity, and not all affected individuals have all of the features associated with the disorder. The average life expectancy is only around 30 years old and many patients require organ transplants in early adulthood; however patients do not always survive following transplantation since their other organs are severely compromised

Some individuals with Alström syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick, dark, and velvety. The signs and symptoms of Alström syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder.

Liminal has shown early efficacy results with a promising drug candidate; PBI-4050. PBI-4050 is an investigational drug currently being tested in an open label clinical trial in the UK and not approved for sale.

Prevalence of Alström Syndrome:

Alström syndrome affects males and females in equal numbers. The exact incidence is unknown. Estimates have ranged from 1 in 10,000 to less than 1 in 1,000,000 individuals in the general population. Approximately 1200 affected individuals have been identified worldwide

Development stage & clinical trial information:

The on-going AS study is an open-label, single-arm, phase 2 clinical trial in which the patients are treated with PBI-4050 (800 mg) once daily. Each patient is evaluated against their respective baseline and against their respective historical disease progression trend whenever available, given the severity of their medical conditions. The clinical study has enrolled 12 subjects.

To date, the subjects have received 52 weeks of treatment with PBI-4050. PBI-4050’s safety and tolerability has been confirmed over this extended period. A brief summary of the most significant findings is presented below.

Fibroscan results from the 10 subjects who received at least 36 weeks of treatment showed a statistically significant improvement in the measure of liver stiffness, from a mean of 10.2 kPa at baseline to a mean of 8.1 kPa at last measurement, an absolute decrease of 2.1 kPa (p = 0.0219, 95% CI -3.52, -0.46). Fibroscan is a non-invasive technique for clinical assessment of liver fibrosis with a high degree of accuracy and reproducibility, especially in patients with established fibrosis (≥ F2) (Cassinotto 2016). FibroScan® measurements for all patients were carried out by a single, experienced operator. To ensure test reliability, a minimum of 10 valid readings were taken per patient, with a required success rate of at least 60% and an interquartile range of <=30% of the median value.

Liver MRI data also indicated a mean reduction of -11% in the T1-corrected score between baseline and last available measurement (p=0.0195, 95% CI: -92.3, -9.8), which supports an improvement of liver fibrosis.

In addition to the preliminary evidence of efficacy observed on liver fibrosis presented above, analysis of the interim cardiac MRI data indicates a reduction of cardiac fibrosis in each patient after initiation of treatment with PBI-4050 (p<0.001).

A major reduction of key urine biomarkers of ongoing kidney injury in the 12 subjects for whom Week 24 results are available was also observed. Finally, positive effects on other parameters of the liver and the fat tissue have also been observed and will be presented at forthcoming scientific conferences.

The Corporation also recently published summary liver and fat biopsies analysis data. Dysfunctional adipose tissue involving enlargement of fat cells, is known to increase cardiometabolic risk. In AS patients, fat tissue is characterized with significant enlargement and coalescence of adipocytes forming giant vesicular vacuolation/steatosis. After 24 weeks of treatment with PBI-4050, adipocytes were more distinct, were smaller in size and no coalescence was observed.

The trial is being performed at the specialty center for the care of UK patients with Alström syndrome at the Queen Elizabeth Hospital, Birmingham, UK. This center has recently published data showing that many of these patients show evidence of non-alcoholic fatty liver disease and advanced liver fibrosis at an early age, confirming previous publications showing a very high incidence of progression of NAFLD into liver cirrhosis with associated mortality in Alström patients.

Clinical Trials